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Abstract

Since the time of the Last Universal Common Ancestor (LUCA), proteins have been the fundamental catalysts of life. For their activity they must assume three-dimensional structures by a complex, easily disrupted, process of folding. However, it is still unclear how the first folded proteins emerged and how life came to rely so extensively on their ability to fold. Our hypothesis is that the first folded proteins resulted from the increased complexity of peptides in the “RNA-peptide world” that preceded LUCA, possibly by three mechanisms 1,2 : repetition, accretion, and recombination. While repetition is one of the most common mechanisms for the emergence of new folded proteins 3, and accretion could already be traced to a few ancient folds 4, recombination is a mechanism harder to trace. Instead of searching for examples of folds that could have their origins in the recombination of at least two ancient fragments, we followed a large-scale computational approach to study whether two such fragments could generate a folded protein when recombined and excluded from their original scaffolds. Using the ribosome as a model of the primordial “RNA-peptide world” 1, we collected a set of ribosomal peptide fragments, which are only folded in the context of the ribosome, and followed an all-against-all molecular docking approach to evaluate their propensity to establish geometrically and energetically compatible inter-faces that would allow the formation of stable, globular, recombinant folds in the absence of the RNA. As a result, we identified multiple ribosomal peptide frag-ment pairs that can recreate not only frequent protein folds but also novel fold topologies and further optimised some of these folds by exploring the sequences of their parent fragments in different organisms. From these, we selected two pairs that are now being experimentally characterised, opening a door to a better understanding of the emergence of the first autonomously folding proteins.